The aim of this study was to evaluate the most common ABCB1 (MDR1, P-glycoprotein) polymorphisms in the population of R. Macedonia and compare the allele and haplotype frequencies with the global geographic data reported from different ethnic populations. The total of 107 healthy Macedonian individuals from the general population was included.
Genotypes for the ABCB1 for three polymorphisms C1236T [rs1128503], G2677A/T [rs2032582] and C3435T [rs1045642] were analyzed by Real-Time PCR. Obtained allele frequencies for these three SNPs were similar to those observed in other European Caucasians. The detected genotype frequencies were 33.6% for 1236CC, 44.9% for 1236CT and 21.5% for 1236TT in exon 12; 32.7%, 44.9% and 22.4% for 2677GG, 2677GT and 2677GT consecutively in exon 21; and 25.2% for 3435CC, 52.3% for 3435CT and 22.5% for 3435TT in exon 26. Strong LD was observed in our study among all three SNPs with the highest association confirmed for C1236T and G2677T ((D' = 0.859, r2 = 0.711). Eight different haplotypes were identified and the most prominent was the CGC haplotype (45.3%). Our study was the first to have documented the distribution of ABCB1 alleles, genotypes and haplotypes in the population of R. Macedonia. The obtained results can help in the prediction of different response to the drugs that are P-glycoprotein substrates. Additionally, in the era of individualized medicine the determination of the P-glycoprotein genotype might be a good predictive marker for determination of the subpopulations with higher risk to certain diseases.
If the inline PDF is not rendering correctly, you can download the PDF file here.
1. Franke R.M. Gardner E.R and A. Sparreboom Pharmacogenetics of Drug Transporters Current Pharmaceutical Desig. 2010; 16: 220-230.
2. Zhu Hao-Jie Wang Jun-Sheng Markowitz SJ Donovan LJ Gibson BB and DeVane CL. Risperidone and Paliperidone Inhibit P-Glycoprotein Activity In Vitro Neuropsychopharmacology. 2007; 32 757-764.
3. Bruhn O Cascorbi I. Polymorphisms of drug transporters ABCB1 ABCG2 ABCC2 and ABCC3 and their impact on drug bioavailability and clinical relevance. Expert Opin Drug Metab Toxicol. 2014; 10: 1337-54.
4. Chandler B Detsika M Khoo SH et al. Factors impacting the expression of membrane-bound proteins in lymphocytes from HIV-positive subjects. J Antimicrob Chemother. 2007; 60: 685-9.
5. Svirnovski AI Shman TV Serhiyenka TF et al. ABCB1 and ABCG2 proteins their functional activity and gene expression in concert with drug sensitivity of leukemia cells. Hematology (Am Soc Hematol Educ Program). 2009; 14: 204-12.
6. Marzolini C Paus E Buclin T and Kim R B. Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance. Clin Pharmacol Ther. 2004; 75 (1): 13-33.
7. Gottesman MM Hrycyna CA Schoenlein PV Germann UA and Pastan I. Genetic analysis of the multidrug transporter. Annu Rev Genet 29; 1995; 607-649.
8. Sugawara I Kataoka K Morishita Y et al. Tissue distribution of P-glycoprotein encoded by a multidrugresistant gene as revealed by a monoclonal antibody. MRK 16. Cancer Res. 48: 1926-1929.
9. Hoffmeyer S Burk O von Richter O Arnold HP Brockmö ller J Johne A et al. Functional polymorphism of the human multidrug-resistance gene: multiple sequence variations and correlations of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci USA. 2000; 97: 3473-3478.
10. Nakamura T Sakaeda T Horinouchi M Tamura T Aoyama N Schirakawa T et al. Effect of the mutation (C3435T) et exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects. Clin Pharmacol Ther. 2002; 71: 297-303.
11. Nikisch G Eap CB and Baumann P. Citalopram enantiomers in plasma and cerebrospinal fluid of ABCB1 genotyped depressive patients and clinical response: a pilot study. Pharmacol Res. 2008; 58: 344-347.
12. Uhr M Grauer MT Yassouridis A and Ebinger M. Blood- brain barrier penetration and pharmacokinetics of amitriptyline and its metabolites in p-glycoprotein (abcb1ab) knock-out mice and controls. J Psychiatr Res. 2007; 41: 179-188.
13. Gex-Fabry M Eap CB Oneda B Gervasoni N Aubry JM Bondolfi G et al. CYP2D6 and ABCB1 genetic variability: Influence on paroxetine plasma level and therapeutic response. Ther Drug Monit 2008; 30: 474-482.
14. Loscher W and Potschka H. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther. 2002; 301: 7-14.
15. Wolf SJ Bachtiar M Wang J Sim TS Chong SS and Lee CGL An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics. The Pharmacogenomics Journal. 2011; 11: 315-325.
16. Tang K Ngoi SM Gwee PC Chua JM Lee EJ Chong SS et al. Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations. Pharmacogenetics. 2002; 12: 437-450.
17. Kim DH Lee NY Sung WJ Baek JH Kim JG Sohn SK et al. Multidrug resistance as a potential prognostic indicator in acute myeloid leukemia with normal karyotypes. Acta Haematol. 2005; 114(2): 78-83.
18. Dulucq S Bouchet S Turcq B Lippert E Etienne G Reiffers J et al. Multidrug resistance gene (MDR1) polymorphisms are associated with major molecular responses to standard-dose imatinib in chronic myeloid leukemia. Blood. 2008; 112: 2024-2027.
19. Ekhart C Rodenhuis S Smits PHM Beijnen JH and Huitem ADR. An overview of the relations between polymorphisms in drug metabolising enzymes and drug transporters and survival after cancer drug treatment. Cancer Treat Rev. 2009; 35: 18-31.
20. Vivona D Bueno CT Lima LT Hirata RDC Hirata MH Luchessi AD et al. ABCB1 haplohaplotype is associated with major molecular response in chronic myeloid leukemia patients treated with standard-dose of imatinib. Blood Cells Mol Dis. 2012; 48: 132-136.
21. Rubis B Holysz H Barczak W Gryczka R Lacinski M et al. Study of ABCB1 polymorphism frequency in breast cancer patients from Poland. Pharmacol Rep. 2012; 64: 1560-1566. 2012.
22. Johne A Kopke K Gerloff T Mai I Rietbrock S Meisel C et al. Modulation of steady-state kinetics of digoxin by haplotypes of the P- glycoprotein MDR1 gene. Clin Pharmacol Ther. 2002; 72(5): 584-94.
23. Chowbay B Cumaraswamy S Cheung YB Zhou Q Lee EJ. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics. 2003; 13(2): 89-95.
24. Yi SY Hong KS Lim HS Chung JY Oh DS Kim JR et al. A variant 2677A allele of the MDR1 gene affects fexofenadine disposition. Clin Pharmacol Ther. 2004; 76(5): 418-27.
25. Tsai CJ Sauna ZE Kimchi-Sarfaty C Ambudkar SV Gottesman MM Nussinov R. Synonymous mutations and ribosome stalling can lead to altered folding pathways and distinct minima. J Mol Biol. 2008; 383: 281-291.
26. Crettol S Deglon JJ Besson J Croquette-Krokar M Hammig R Gothuey I et al. ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment. Clin Pharmacol Ther. 2006; 80: 668-681.
27. Shi YY He L. SHEsis a powerful software platform for analyses of linkage disequilibrium haplotype construction and genetic association at polymorphism loci. Cell Res. 2005; 15(2): 97-8.
28. Li Z Zhang Z He Z Tang W Li T Zeng Z et al. A partition-ligation-combination-subdivision EM algorithm for haplotype inference with multiallelic markers: update of the SHEsis (http://analysis.bio-x-cn). Cell Res. 2009; 19(4): 519-23.
29. Sai K Kaniwa N Itoda M Saito Y Hasegawa R Komamura et al. Haplotype analysis of ABCB1- MDR1 blocks in a Japanese population reveals genotype- dependent renal clearance of irinotecan. Pharmacogenetics. 2003; 13: 741-757.
30. Wasilewska A Zalewski G Chyczewski L and Zoch-Zwierz W. MDR1 gene polymorphisms and clinical course of steroid-responsive nephrotic syndrome in children. Pediatr Nephrol. 2007; 22: 44-51.
31. Xu P Jiang ZP Zhang BK Tu JY and Li HD. Impact of MDR1 haplotypes derived from C1236T G2677T=A and C3435T on the pharmacokinetics of single-dose oral digoxin in healthy Chinese volunteers. Pharmacology. 2008; 82: 221-227.
32. Pechandova D Buzkova K H Slanar O and Perlík F. Polymorphisms of the MDR1 gene in the Czech population. Folia Biol (Praha). 2006; 52: 184-189.
33. Komoto C Nakamura T Sakaeda T Kroetz DL Yamada T et al. MDR1 haplotype frequencies in Japanese and Caucasian and in Japanese patients with colorectal cancer and esophageal cancer. Drug Metab Pharmacokinet. 2006; 21: 126-132.
34. Lee SS Kim SY Kim WY Thi-Le H Yoon YR Yea SS and Shin JG. MDR1 genetic polymorphisms and comparison of MDR1 haplotype profiles in Korean and Vietnamese populations. Ther Drug Monit. 2005; 27: 531-535.
35. Halim Salem A Ali M Ibrahim A and Ibrahim M. Genotype and Allele Frequencies of MDR-1 Gene Polymorphism in Jordanian and Sudanese Populations American Journal of Medicine Studies. 2014; 1: 19-23.
36. Gonzalez TP Mucenic T Brenol JC Xavier RM Schiengold M Chies JA. ABCB1 C1236T G2677T/A and C3435T polymorphisms in systemic lupus erythematosus patients. Braz J Med Biol Res. 2008; 41(9): 769-72.
37. Sipeky C Csongei V Jaromi L Safrany E Maasz A Takacs I et al. Genetic variability and haplotype profile of MDR1 (ABCB1) in Roma and Hungarian population samples with a review of the literature. Drug Metab Pharmacokinet. 2011; 26(2): 206-15.
38. Marie-Genica Consortium on Genetic Susceptibility for Menopausal Hormone Therapy Related Breast Cancer Risk. “Polymorphisms in the BRCA1 and ABCB1 genes modulate menopausal hormone therapy associated breast cancer risk in postmenopausal women. Breast Cancer Res Treat. 2010; 120 (3): 727-736.
39. Kafka A Sauer G Jaeger C Grundmann R Kreienberg R Zeillinger R Deissler H. Polymorphism C3435T of the MDR-1 gene predicts response to preoperative chemotherapy in locally advanced breast cancer. Int J Oncol. 2003; 22(5): 1117-21.
40. Simon T Verstuyft C Mary-Krause M Quteineh L Drouet E Meneveau N et al. Genetic determinants of esponse to clopidogrel and cardiovascular events. N Engl J Med. 2009; 360 (4): 363-375.
41. Kim DH Park JY Sohn SK Lee NY Baek JH Jeon SB et al. Multidrugresistence-1 gene polymorphisms associated with treatment outcomes in de novo acute myeloid leukemia. Int J Cancer. 2006; 118(9): 2195- 201.
42. Siddiqui A Kerb R Weale ME Brinkmann U Smith A Goldstein DB et al. Association of multidrug resistance in epilepsy with a polymorphism in the drugtransporter gene ABCB1. N Engl J Med. 2003; 348(15): 1442-8.
43. E Shon JH Yoon YR Hong WS Nguyen PM Lee SS Choi YG et al. Effect of itraconazole on the pharmacokinetics and pharmacodynamics of fexofenadine in relation to the MDR1 genetic polymorphism. Clin Pharmacol Ther. 2005; 78: 191-201.
44. F Cavaco I Gil JP Gil-Berglund E and Ribeiro V. CYP3A4 and MDR1 alleles in a Portuguese population. Clin Chem Lab Med. 2003; 41: 1345-1350.
45. Pan JH Han JX Wu JM Huang HN Yu QZ and Sheng LJ. MDR1 single nucleotide polymorphism G2677T=A and haplotype are correlated with response to docetaxelcisplatin chemotherapy in patients with non-small-cell lung cancer. Respiration. 2009; 78: 49-55.
46. Potocnik U Glavac D and Dean M. Common germline MDR1/ABCB1 functional polymorphisms and haplotypes modify susceptibility to colorectal cancers with high microsatellite instability. Cancer Genet Cytogenet. 2008; 183: 28-34.
47. Wang D Johnson AD Papp AC Kroetz DL and Sadee W. Multidrug resistance polypeptide 1 (MDR1 ABCB1) variant 3435C T affects mRNA stability. Pharmacogenet. Genomics. 2005; 15: 693-704.
48. Kim RB Leake BF Choo EF. et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin. Pharmacol. Ther. 2001; 70: 189-199.
49. Urayama KY Wiencke JK Buffler PA Chokkalingam AP Metayer C and Wiemels JL. MDR1 gene variants indoor insecticide exposure and the risk of childhood acute lymphoblastic leukemia. Cancer Epidemiol Biomarkers Prev. 2007; 16: 1172-1177.
50. Kurzawski M Pawlik A Gornik W and Drozdzik M. Frequency of common MDR1 gene variants in a Polish population. Pharmacol. Rep. 2006; 58: 35-40.
51. Kroetz DL Pauli-Magnus C Hodges LM. et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1 multidrug resistance transporter) gene. Pharmacogenetics. 2003; 13: 481-494.
52. Gümüş-Akay G Rüstemoğlu A Karadağ A Sunguroğlu A. Haplotype-based analysis of MDR1/ABCB1 gene polymorphisms in a Turkish population. DNA Cell Biol. 2010; 29: 83-90.
53. Bandur S Petrasek J Hribova P Novotna E Brabcova I and Viklicky O. Haplotypic structure of ABCB1/MDR1 gene modifies the risk of the acute allograft rejection in renal transplant recipients. Transplantation. 2008; 86(9): 1206-13.
54. Wong M Evans S Rivory LP Hoskins JM Mann GJ Farlow D et al. Hepatic technetium Tc 99mlabeled sestamibi elimination rate and ABCB1 (MDR1) genotype as indicators of ABCB1 (P-glycoprotein) activity in patients with cancer. Clin Pharmacol Ther. 2005; 77(1): 33-42.
55. Panczyk M Balcerczak E Piaskowski S Jamroziak K Pasz-Walczak G Mirowski M. ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer. Int J Colorectal Dis. 2009; 24(8): 895-905.
56. Sai K Kaniwa N Itoda M Saito Y Hasegawa R Komamura K et al. Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan. Pharmacogenetics. 2003; 13(12): 741-57.
57. Cascorbi I. Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs. Pharmacol. Ther. 2006; 112: 457-473.
58. Tan E.K Drozdzik M Bialecka M. et al. Analysis of MDR1 haplotypes in Parkinson's disease in a white population. Neurosci. Lett. 2004; 372: 240-244.
59. Gaikovitch EA Cascorbi I Mrozikiewicz PM et al. Polymorphisms of drug-metabolizing enzymes CYP2C9 CYP2C19 CYP2D6 CYP1A1 NAT2 and of P-glycoprotein in a Russian population. Eur. J. Clin. Pharmacol. 2003; 59: 303-312.
60. Ameyaw MM Regateiro F Li T. et al. MDR1 pharmacogenetics: frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity. Pharmacogenetics 2001; 11: 217-221.
61. Onnie CM Fisher SA Pattni R Sanderson J Forbes A Lewis CM Mathew CG. Associations of allelic variants of the multidrug resistance gene (ABCB1 or MDR1) and inflammatory bowel disease and their effects on disease behavior: a case-control and meta-analysis study. Inflamm Bowel Dis. 2006; 12(4): 263-71.
62. Ho GT Nimmo ER Tenesa A et al. Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology. 2005; 128: 288-296.
63. Jeannessona E Albertinia L Siesta G Gomesb AM Ribeirob V Aslanidisc C et al. Determination of ABCB1 polymorphisms and haplotypes frequencies in a French population Fundamental and Clinical Pharmacology. 2007; 21: 411-41864. Bernal ML Sinues B Fanlo A and Mayayo E. Frequency distribution of C3435T mutation in exon 26 of the MDR1 gene in a Spanish population. Ther. Drug Monit. 2003; 25: 107-111.
65. Vicente J Sinues B Fanlo A Vasquez P Medina JC Martinez-Jarreta B. Polymorphism C3435T of the MDR1 gene in Central Americans and Spaniards. Mol Biol Rep. 2008; 35(3): 473-8.
66. Furuno T Landi MT Ceroni M et al. Expression polymorphism of the blood-brain barrier component Pglycoprotein (MDR1) in relation to Parkinson's disease. Pharmacogenetics. 2002; 12: 529-534.
67. Palmieri O Latiano A Valvano R D'Incà R Vecchi M Sturniolo GC Saibeni S et al. Multidrug resistance 1 gene polymorphisms are not associated with inflammatory bowel disease and response to therapy in Italian patients. Aliment Pharmacol Ther. 2005; 22(11-12): 1129-38.
68. Petrova DT Nedeva P Maslyankov S Toshev S Yaramov N Atanasova S et al. No association between MDR1 (ABCB1) 2677G > T and 3435C > T polymorphism and sporadic colorectal cancer among Bulgarian patients. Cancer Res Clin Oncol. 2008; 134(3): 317-22.
69. Milojkovic M Stojnev S Jovanovic I Ljubisavljevic S Stefanovic V Sunder-Plassman R. Frequency of the C1236T G2677T/A and C3435T MDR1 gene polymorphisms in the Serbian population. Pharmacol Rep. 2011; 63(3): 808-14.
70. Sabahi Z Salek R Heravi R Mosaffa F Avanaki Z and Behravan J. Association of gastric cancer incidence with MDR1 gene polymorphism in an ethnic Iranian population. Indian J Cancer. 2010; 47: 317-321.
71. Hamdy S I Hiratsuka M Narahara K Endo N El- Enany M Moursi N et al. Genotype and allele frequencies of TPMT NAT2 GST SULT1A1 and MDR-1 in the Egyptian population. Br J Clin Pharmacol. 2003; 55: 560-569.
72. Sapmaz A Ozen Karatayli SC Dağli U Kiliç ZM Törüner M Celik Y et al. Effects of polymorphism in G2677T/A triallelic region of MDR1 gene in Turkish patients with inflammatory bowel disease. Turk J Gastroenterol. 2008; 19(3): 168-73.
73. Omoto CK Akamura TN Akaeda TS Roetz DLK Amada TY Matsu HO et al. Regular article MDR1 haplotype frequencies in Japanese and Caucasian and in Japanese patients with colorectal cancer and esophageal cancer. Drug Metab Pharmacokinet. 2006; 21: 126-132.
74. Horinouchi M Sakaeda T Nakamura T Morita Y Tamura T Aoyama N et al. Significant genetic linkage of MDR1 polymorphisms at positions 3435 and 2677: functional relevance to pharmacokinetics of digoxin. Pharm Res. 2002; 19(10): 1581-5.
75. Zheng H Webber S Zeevi A Schuetz E Zhang J Lamba J et al. The MDR1 polymorphisms at exons 21 and 26 predict steroid weaning in pediatric heart transplant patients. Human Immunol. 2002; 63: 765- 770.
76. Li D Zhang GL Lou YQ Li Q Wang X Bu XY. Genetic polymorphisms in MDR1 and CYP3A5 haplotype in mainland Chinese Han Uygur and Kazakh ethnic groups. J Clin Pharm Ther. 2007; 32(1): 89-95.
77. Zhang WX Chen GL Zhang W Tan ZR Liu J Zhou G et al. MDR1 genotype do not influence tha absorption of a single oral dose of 100 mg talinolol in healthy Chinese males. Clin Chim Acta. 2005; 359(1- 2): 46-52.
78. Kassogue Y Dehbi H Nassereddine S Quachouh M and Nadifi S. Genotype Variability and Haplotype Frequency of MDR1 (ABCB1) Gene Polymorphism in Morocco. DNA and Cell biology. 2013; 32(10): 582-8.
80. Kimchi-Sarfaty C Marple AH Shinar S Kimchi AM Scavo D Roma MI et al. Ethnicity-related polymorphisms and haplotypes in human ABCB1 gene. Pharmacogenomics. 2007; 8(1): 29-39.
81. Estrela RC Ribeiro FS Carvalho RS Gregório SP Dias-Neto E Struchiner CJ Suarez-Kurtz G. Distribution of ABCB1 polymorphisms among Brazilians: impact of population admixture. Pharmacogenomics. 2008; 9(3): 267-76.